Dr. Smith: Welcome to The ASCO Post Roundtable Series on Updates in Prostate Cancer. I'm Dr. Matthew Smith from the Massachusetts General Hospital Cancer Center in Boston. Joining me today are two of my colleagues.
Dr. Gao: Hi, my name is Xin Gao. I'm an instructor in medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital in Boston.
Dr. Morgans: Hi, my name is Alicia Morgans and I'm a GU medical oncologist and associate professor of medicine at Northwestern University in Chicago.
Dr. Smith: Dr. Gao and Dr. Morgans, thank you for joining me today. We're going to be discussing recent updates in prostate cancer, including data presented at the 2021 ASCO Annual Meeting, and integrating these new developments into four patient case studies. Our fourth installment will focus on the emerging role of PSMA targeted therapy in metastatic castration-resistant prostate cancer.
In this case, we have a 67-year-old man with metastatic castration-resistant prostate cancer, or mCRPC. He has disease progression following abiraterone acetate plus prednisone and subsequent treatment with docetaxel. He reports intermittent bone pain that is reasonably well controlled with NSAIDs. His latest PSA is 89, and PSMA PET CT demonstrates extensive bone metastasis as well as para-aortic adenopathy with the largest lymph node measuring 1.5 cm. His past medical history includes hypertension and diabetes mellitus. What do you recommend in managing this patient as the next step? Cabazitaxel, radium 223, or 177 lutetium PSMA 617, which we’ll referred to as PSMA 617. Dr. Goa, what is your opinion about this case?
Dr. Gao: Thanks, Matthew. So this is a patient with fairly treatment-refractory metastatic castration-resistant prostate cancer. He's been through abiraterone, a novel hormonal therapy, as well as chemotherapy with docetaxel. In terms of these treatment choices between cabazitaxel, radium 223, and PSMA 617, I think they are all options that should be considered here. And I would discuss with the patient the data surrounding these therapies, the toxicities, the treatment logistics and schedules that are involved, and talk about the pros and cons. None of these have been really compared robustly; we don't have robust more long-term data comparing these therapies. And so I think all of these are options.
Now, personally, I'm pretty excited and intrigued about the data from the VISION trial that was just presented at ASCO in June 2021, with regards to the PSMA 617 therapy. This is a radiotherapeutic targeting prostate-specific membrane antigen, which is highly expressed on the vast majority of prostate cancers. So on that trial, the VISION trial, they used PSMA PET imaging as a baseline screening, and the positivity rate was 87%. So the vast majority of patients screened positive into this study. And lutetium PSMA 617 showed a benefit in terms of both overall survival as well as radiographic progression-free survival. The hazard ratio for overall survival was in the 0.6 range, pretty similar to many of our other therapies in this space. The therapy is given once every 6 weeks for four cycles. And for those patients who had a response but still had some residual disease, an additional two cycles of therapy was allowed. And so I think the logistics of this treatment can be pretty favorable for certain patients.
Dr. Smith: Thank you, Dr. Gao. Dr. Morgans, assuming PSMA 617 is available, what would you choose in a patient like this and why?
Dr. Morgans: Well, to Dr. Gao's point, these are all reasonable options. So I would certainly talk to patients about the choices that they have, but I think given the relatively gentle toxicity profile, I would probably steer the patient in the direction of PSMA 617. Interestingly and importantly, not presented at ASCO 2021, but presented previously, the TheraP trial did compare in a phase II trial patients who had mCRPC, who had already had progression on an AR-targeted agent and docetaxel, and they were randomized to treatment with cabazitaxel versus PSMA 617. And this study really demonstrated at least that PSMA 617 had a more robust PSA response than cabazitaxel and also seemed to have a favorable toxicity profile with fewer patients having a grade > 3 adverse events by CTCAE—the criteria that we typically use in clinical trials to understand the severity of those adverse events.
Importantly, I think we have to recognize that no therapy comes without some adverse events. Patients who have significant cytopenias can certainly have challenges with PSMA 617, including thrombocytopenia, which seemed to be more common in the PSMA 617 patients than in patients treated with cabazitaxel. But generally, other than that, and some xerostomia, patients seemed to tolerate the treatment well, and there seemed to be a really nice disease control response, making lutetium PSMA 617, a reasonable option for patients. But, of course, as we mentioned, they all really are options. And it's nice to have the ability to offer to patients. These are your choices, these are my suggestions, but let the patient actually decide.
Dr. Smith: Yeah, I agree. So just briefly review the data from the VISION trial, it's so new presented at ASCO Annual Meeting. So this was an open-label study for patients with PSMA PET-positive mCRPC, as both of you noted had prior progression after at least one AR pathway inhibitor and at least one taxane. They had to have the PSMA PET positive. And as Dr. Goa noted that 87% screened positive by that criteria. Patients were randomized to best standard of care or best standard of care plus PSMA 617 for up to six cycles and then were followed for rPFS and OS. And as was noted, there was a statistically significant and clinically meaningful improvement in overall survival from a median of 11.3 months in the control group to 15.3 months in the PSMA 617 group for a hazard ratio of 0.62. So very comparable to our best approved therapies in mCRPC.
And then there was a large improvement in rPFS with that hazard ratio of 0.40 and an improvement from 3.4 months to 8.7 months in favor of PSMA 617. As noted by our faculty, treatment comes at the cost of side effects, and consistent with the earlier experience with PSMA 617, treatment with that agent was associated with a higher rate of any treatment-emergent adverse events or serious adverse events compared to standard of care alone, with the most commonly reported adverse events, being fatigue, bone marrow suppression, including thrombocytopenia, dry mouth, nausea, and vomiting.
I guess I'd like to ask the faculty, does this safety profile, in any way, impact your thinking about sequencing of therapy? Are there patients, I mean—Dr. Morgans you already commented on this briefly, but could you expand? Is this going to preclude treatment with this agent in certain patients, or will this safety profile impact your thinking about what's the most appropriate next treatment?
Dr. Morgans: So just to make a quick comment on the VISION trial safety and adverse events too, though. We should know that this was a randomization, not against chemotherapy, not against radium. This was really best supportive care. So when we think about having more cytopenias against best supportive care, that actually is going to happen with things like AR-targeted agents. But certainly when we are randomizing against things like chemotherapy or radium, we may have similar adverse events in terms of cytopenias. So I think that should be recognized when we look at the age profile of VISION specifically, just understanding what we are comparing this to.
But when we think about actually using this medication in our practices, absolutely I think the cytopenias may be the biggest barrier to treatment, because especially as patients become more and more advanced in terms of their disease burden, they really can have significant marrow infiltration and cytopenias that come, not just from prior therapies, but prior therapy certainly affects bone marrow, but also from disease infiltration into the marrow really preventing production. So I think that ultimately moving things like PSMA 617 forward will give us a better opportunity to not be limited by cytopenias, but that patients with pre-existing bone marrow suppression are probably the ones that I'm most concerned about in terms of choosing that treatment approach.
Dr. Smith: Yeah, agreed. The patients, appropriately in the VISION trial, where patients with very advanced disease, where you're going to expect a high rate of adverse events and less marrow reserve and sort of pretest probability or expectation that you're going to see marrow toxicity with an agent like this. And I wholeheartedly agree that we all look forward to gaining additional personal experience with this agent, as well as seeing this drug potentially move earlier based on the results of ongoing and future clinical trials.
So let me briefly summarize, based on this case, the data from the VISION trial, and comments from the faculty. So in patients with PSMA PET-positive mCRPC and disease progression, after prior taxane and NHT, the addition of PSMA 617 improved progression-free and overall survival compared to standard of care alone. The most commonly reported adverse effects of this agent were fatigue, bone marrow, suppression, dry mouth, nausea, and vomiting. And then as you've heard ongoing and planned studies will evaluate PSMA targeted therapy, including [PSMA] 617 in other earlier disease states in prostate cancer.
This brings us to the end of this case. Please see the other segments for further discussion about the latest data in prostate cancer or visit ascopost.com.